This invention pertains generally to treating diseases characterized by angiogenesis including cancer. More specifically, the invention described herein pertains to treating diseases characterized by activity of vascular endothelial growth factor receptor tyrosine kinases. The present invention provides small molecule inhibitors of vascular endothelial growth factor receptor tyrosine kinase, pharmaceutical formulations containing such inhibitors, methods of treating patients with such pharmaceutical formulations, and to methods of preparing such pharmaceutical formulations and inhibitors.
Capillaries reach into almost all tissues of the human body and supply tissues with oxygen and nutrients as well as removing waste products. Under typical conditions, the endothelial cells lining the capillaries do not divide, and capillaries, therefore, do not normally increase in number or size in a human adult. Under certain normal conditions, however, such as when a tissue is damaged, or during certain parts of the menstrual cycle, the capillaries begin to proliferate rapidly. This process of forming new capillaries from pre-existing blood vessels is known as angiogenesis or neovascularization. See Folkman, J. Scientific American 275, 150-154 (1996). Angiogenesis during wound healing is an example of pathophysiological neovascularization during adult life. During wound healing, the additional capillaries provide a supply of oxygen and nutrients, promote granulation tissue, and aid in waste removal. After termination of the healing process, the capillaries normally regress. Lymboussaki, A. xe2x80x9cVascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumorsxe2x80x9d Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999).
Angiogenesis also plays an important role in the growth of cancer cells. It is known that once a nest of cancer cells reaches a certain size, roughly 1 to 2 mm in diameter, the cancer cells must develop a blood supply in order for the tumor to grow larger as diffusion will not be sufficient to supply the cancer cells with enough oxygen and nutrients. Thus, inhibition of angiogenesis is expected to retard or halt the growth of cancer cells.
Receptor tyrosine kinases (RTKs) are transmembrane polypeptides that regulate developmental cell growth and differentiation and remodeling and regeneration of adult tissues. Mustonen, T. et al., J. Cell Biology 129, 895-898 (1995); van der Geer, P. et al. Ann Rev. Cell Biol. 10, 251-337 (1994). Polypeptide ligands known as growth factors, or cytokines, are known to activate RTKs. Signaling of RTKs involves ligand binding and a shift in conformation in the external domain of the receptor resulting in its dimerization. Lymboussaki, A. xe2x80x9cVascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumorsxe2x80x9d Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999); Ullrich, A. et al., Cell 61, 203-212 (1990). Binding of the ligand to the RTK results in receptor trans-phosphorylation at specific tyrosine residues and subsequent activation of the catalytic domains for the phosphorylation of cytoplasmic substrates. Id.
Two subfamilies of RTKs are specific to the vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily. Class III RTKs include VEGFR-1, VEGFR-2, and VEGFR-3. Shibuya, M. et al., Oncogene 5, 519-525 (1990); Terman, B. et al., Oncogene 6, 1677-1683 (1991); Aprelikova, O. et al., Cancer Res. 52, 746-748 (1992).
Members of the VEGF subfamily have been described as being able to induce vascular permeability and endothelial cell proliferation and further identified as a major inducer of angiogenesis and vasculogenesis. Ferrara, N. et al., Endocrinol. Rev. 18, 4-25 (1997). VEGF is known to specifically bind to RTKs including VEGFR-1 and VEGFR-2. DeVries, C. et al., Science 255, 989-991 (1992); Quinn, T. et al., Proc. Natl. Acad. Sci. 90, 7533-7537 (1993). VEGF stimulates the migration and proliferation of endothelial cells and induces angiogenesis both in vitro and in vivo. Connolly, D. et al., J. Biol. Chem. 264, 20017-20024 (1989); Connolly, D. et al., J. Clin. Invest. 84, 1470-1478 (1989); Ferrara, N. et al., Endocrino. Rew. 18, 4-25 (1997); Leung, D. et al., Science 246, 1306-1309 (1989); Plouet, J. et al., EMBO J 8, 3801-3806 (1989).
Because angiogenesis is known to be critical to the growth of cancer and to be controlled by VEGF and VEGF-RTK, substantial efforts have been undertaken to develop therapeutics that are antagonists of VEGF-RTK to thereby inhibit or retard angiogenesis, and hopefully interfere or stop tumor proliferation.
A wide variety of chemical compounds and compositions have been reported as having activity against one of more the VEGF-RTKs. Examples include quinoline derivatives such as described in WO 98/13350, aminonicotinamide derivatives (see, e.g., WO 01/55114), antisense compounds (see, e.g., WO 01/52904), peptidomimetics (see, e.g., WO 01/52875), quinazoline derivatives (see, e.g., U.S. Pat. No. 6,258,951) monoclonal antibodies (see, e.g., EP 1 086 705 A1), various 5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see, e.g., WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acid derivatives (see, e.g., DE19841985), oxindolylquinazoline derivatives (see, e.g., WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g., U.S. Pat. No. 5,763,441), and cinnoline derivatives (see, e.g., WO 97/34876), and various indazole compounds (see e.g., WO 01/02369 and WO 01/02369).
Various indolyl-substituted compounds have recently been disclosed in WO 01/29025, and various benzimidazolyl compounds have recently been disclosed in WO 01/28993. These compounds are reportedly capable of inhibiting, modulating, and/or regulating signal transduction of both receptor-type and non-receptor tyrosine kinases. Some of the disclosed compounds contain a quinolone fragment bonded to the indolyl or benzimidazolyl group.
The synthesis of 4-hydroxy quinolone and 4-hydroxy quinoline derivatives is disclosed in a number of references. For example, Ukrainets et al. have disclosed the synthesis of 3-(Benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets, I. et al., Tet. Lett. 42, 7747-7748 (1995); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241(1992). Ukrainets has also disclosed the synthesis, anticonvulsive and antithyroid activity of other 4-hydroxy quinolones and thio analogs such as 1H-2-oxo-3-(2-benzimidazolyl)-4-hyrdoxyquinoline. Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 1, 105-108 (1993); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993); Ukrainets, I. et al., Chem. Heterocyclic Comp. 33, 600-604, (1997).
The synthesis of various quinoline derivatives is disclosed in WO 97/48694. These compounds are disclosed as capable of binding to nuclear hormone receptors and being useful for stimulating osteoblast proliferation and bone growth. The compounds are also disclosed as being useful in the treatment or prevention of diseases associated with nuclear hormone receptor families.
Various quinoline derivatives in which the benzene ring of the quinolone is substituted with a sulfur group are disclosed in WO 92/18483. These compounds are disclosed as being useful in pharmaceutical formulations and as medicaments.
Quinolone and coumarin derivatives have been disclosed as having use in a variety of applications unrelated to medicine and pharmaceutical formulations. References that describe the preparation of quinolone derivatives for use in photopolymerizable compositions or for luminescent properties include: U.S. Pat. No. 5,801,212 issued to Okamoto et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP 797376; and DE 23 63 459.
Despite the exploration of a variety of chemistries to provide VEGF-RTK-antagonist therapies, a continuing need exists for compounds that inhibit the proliferation of capillaries, inhibit the growth of tumors, and/or inhibit vascular endothelial growth factor receptor tyrosine kinase and pharmaceutical formulations that contain such compounds. A need also exists for methods for administering such compounds and pharmaceutical formulations to patients in need thereof.
The present invention provides compounds, pharmaceutical formulations including the compounds, methods of preparing the pharmaceutical formulations, and methods of treating patients with the pharmaceutical formulations and compounds.
The present invention provides compounds having the structure I. The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure I has the following formula: 
where:
Y is selected from xe2x80x94OH, xe2x80x94OR8 groups, xe2x80x94SH, xe2x80x94SR9 groups, xe2x80x94NR10R11 groups, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R12 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
Z is O, S, or a NR13 group;
R1 and R2 join to form a 5 to 7 membered substituted or unsubstituted ring including at least one O, N, or S atom;
R3 and R13 may be the same or different and are selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted diheterocyclylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted (aryl)(heterocyclyl)amino groups, substituted and unsubstituted heterocylyloxy groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R4, R5, R6, and R7 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OR14 groups, xe2x80x94NR15R16 groups, xe2x80x94C(xe2x95x90O)R17 groups, 13 SH, xe2x80x94SR18 groups, xe2x80x94S(xe2x95x90O)R19 groups, S(xe2x95x90O)2R20 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R8 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R9 and R18 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups;
R10 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R11 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R12 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or xe2x80x94N(aryl)(heterocyclyl) groups;
R14 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)NH-heterocyclyl groups, xe2x80x94C(xe2x95x90O)N-(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R15 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R16 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; and
R17, R19, and R20 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted aryl groups, xe2x80x94OH, substituted and unsubstituted alkoxy groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted aryloxy groups, heterocyclyloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, and xe2x80x94N(aryl)O-aryl groups.
Preferred compounds having the structure I are provided where Y is selected from xe2x80x94OH, xe2x80x94OR8 groups, or xe2x80x94NR10R11 groups, or more preferably is a xe2x80x94NR10R11 group.
Still other preferred compounds having the structure I are provided in which Z is an NR13 group and the rest of the compound is consistent with any of the above-described compounds.
In still other preferred compounds of structure I, R4 and R7 are hydrogen, R6 and R7 are selected from hydrogen or an alkyl group having from 1 to 4 carbon atoms, and the rest of the compound is consistent with any of the above-described compounds.
Still other compounds having the formula of structure I are provided in which R5 or R6 is an xe2x80x94OR14 group and R14 is an alkyl, aryl, heterocyclyl, or heterocyclylalkyl group and the rest of the molecule is consistent with any of the above-described compounds.
In still further preferred compounds having the formula of structure I, R5 or R6 is a xe2x80x94OCH2(CH2)q(heterocyclyl) group where q is 0, 1, 2, 3, or 4 and the rest of the compound is consistent with any of the above-described compounds.
Other preferred compounds having the structure I are provided in which R17 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, or N-containing heterocycles, and the N-containing heterocycles are bonded to the carbonyl carbon of the xe2x80x94C(xe2x95x90O)xe2x80x94R17 group through either a nitrogen atom or a carbon atom in the rings of the N-containing heterocycles.
The present invention also provides compounds having the structure III. The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure III has the following formula: 
where:
W1, W2, W3, and W4 are selected from C or N, and at least one of W1, W2, W3, or W4 is N;
X1, X2, X3, and X4 are selected from C or N, and at least one of X1, X2, X3, or X4 is N;
Y is selected from H, xe2x80x94OH, xe2x80x94OR10 groups, xe2x80x94SH, xe2x80x94SR11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R14 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R1, R2, R3, R4, R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, xe2x80x94C(xe2x95x90O)R18 groups, xe2x80x94SH, xe2x80x94SR19 groups, xe2x80x94S(xe2x95x90O)R20 groups, S(xe2x95x90O)2R19 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups, substituted and unsubstituted (aryl)(heterocyclyl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups, and R1 is absent or H if W1 is N, R2 is absent or H if W2 is N, R3 is absent or H if W3 is N, R4 is absent or H if W4 is N, R5 is absent or H if X1 is N, R6 is absent or H if X2 is N, R7 is absent or H if X3 is N, and R8 is absent or H if X4 is N;
R9 is selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R10 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R14 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or xe2x80x94N(aryl)(heterocyclyl) groups;
R15 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94(Cxe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)NH-heterocyclyl groups, xe2x80x94C(xe2x95x90O)N-(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted and unsubstituted diheterocyclylaminoalkyl groups, substituted and unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; and
R18, R20, and R21 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryloxy groups, heterocyclyloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, and xe2x80x94N(aryl)O-aryl groups.
Preferred compounds having structure III are also provided where one of W1, W2, W3, or W4 is N.
Preferred compounds having structure III are also provided where one of X1, X2, X3, or X4 is N.
Preferred compounds having structure III are also provided where Y is selected from H, xe2x80x94OH, xe2x80x94OR10 groups, or xe2x80x94NR12R13 groups, or more preferably is a xe2x80x94NR12R13 group.
Still other preferred compounds having structure III are provided where R5 is H, X4 is N, R6 and R7 are selected from H or alkyl groups having from one to four carbon atoms, and the rest of the compound is consistent with any of the above-described compounds.
Still other compounds of structure III are provided in which R6 or R7 is an xe2x80x94OR15 group and R15 is an alkyl, aryl, heterocyclyl, or heterocyclylalkyl group and the rest of the molecule is consistent with any of the above-described compounds.
In still further preferred compounds of structure III, R6 or R7 is a xe2x80x94OCH2(CH2)q(heterocyclyl) group, q is 0, 1, 2, 3, or 4, and the rest of the compound is consistent with any of the above-described compounds.
Other preferred compounds having the structure III are provided in which R18 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, or N-containing heterocycles, and the N-containing heterocycles are bonded to the carbonyl carbon of the xe2x80x94C(xe2x95x90O)xe2x80x94R18 group through either a nitrogen atom or a carbon atom in the rings of the N-containing heterocycles.
Pharmaceutical formulations according to the present invention are provided which include any of the compounds described above in combination with a pharmaceutically acceptable carrier.
A method of treating a patient in need of an inhibitor of vascular endothelial growth factor receptor tyrosine kinase is provided which includes administering an effective amount of the pharmaceutical formulation according to the present invention to a patient in need thereof.
Further objects, features and advantages of the invention will be apparent from the following detailed description.